Dysregulation of vitamin D metabolism can lead to several diseases including hypercalcemia, secondary hyperparathyroidism, hypocalcemia, hypophosphatemia, rickets, osteomalacia and growth retardation. The bioactive form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25D), is made by the enzyme Cyp27b1 (25- dihydroxyvitamin D 1-alpha hydroxylase). Renal Cyp27b1 has long been considered the primary source of circulating 1,25D. This 40-year principle was established mainly from the observation that decreased renal function is strongly associated with decreased serum 1,25D levels in anephric animal models and patients with chronic kidney disease. It is well known that parathyroid hormone (PTH) activates its renal receptors to increase Cyp27b1 expression, and subsequently, to elevate serum 1,25D levels. However, these paradigms fit basic observations that do not take into account the fact that many tissues express the 1-alpha hydroxylase and generate 1,25D. Our preliminary studies in mice with vitamin D receptor (VDR) or Cyp27b1 gene knockout targeted specifically to parathyroid cells suggest that the Cyp27b1 expressed in parathyroid gland (PTG) could be a major source of circulating 1,25D and exert endocrine actions on mineral and skeletal homeostasis. We further found that the incubation of freshly isolated mouse PTGs with PTH(1-34) profoundly increased Cyp27b1 protein and RNA in these PTGs, indicating direct regulation of this enzyme by PTH. The above studies together led us to hypothesize that the parathyroid Cyp27b1 is a prominent source of circulating 1,25D that is subject to direct regulation by PTH and other hormonal and mineral factors. To test this hypothesis we will (1) determine the hormonal, mineral, and skeletal actions of PT-derived Cyp27b1 in the mouse model, and (2) determine the mechanisms and systemic factors that regulate Cyp27b1 expression and function in the PTG. Successful completion of this fellowship project will lend support to new regulatory paradigms for vitamin D and mineral metabolism and will provide me with essential training in parathyroid physiology, cell biology, vitamin D metabolism and mouse genetics, and will expand my technical skills in my development as an independent research scientist.